4-pyridinone compounds and their use for cancer

ABSTRACT

Disclosed herein is a process for preparing a compound of Formula (I), comprising the steps of: (a) reacting an aniline compound of Formula (II) and an carboxylic acid compound of Formula (III) or an activated carboxylic acid compound thereof, to provide a compound of Formula (IV); and (b) converting said protected amine group attached to said compound of Formula (IV) to an amine group to provide said compound of Formula (I); wherein PAm is a protected amine group. Processes to prepare the compounds of Formulae (II), (III), and (IV) are also disclosed.

The present invention generally relates to processes for preparingpyridinone compounds.

Met, also referred to as hepatocyte growth factor receptor (HGFR), isexpressed predominantly in epithelial cells but has also been identifiedin endothelial cells, myoblasts, hematopoietic cells, and motor neurons.Overexpression of hepatocyte growth factor and activation of Met hasbeen associated with the onset and progression in a number of differenttumor types as well as in the promotion of metastatic disease.

U.S. Patent Application Publication 2008/0114033 A1 discloses apyridinone compound useful for treating Met-related cancers. Thedisclosed pyridinone compound, which comprises an amide linkage and anamine substituted pyridyl group, has the structure of Formula (Ia):

The reference also discloses a multistep synthesis process for preparingthe pyridinone compound. This process includes the reaction between ananiline compound and a carboxylic acid compound to form the amidelinkage in the compound of Formula (Ia). The disclosed process alsoincludes a Hofmann Rearrangement reaction to convert an amidesubstituent to an amine group, to provide the amine substituted pyridylgroup in the structure of Formula (Ia).

There are difficulties associated with the adaptation of the multistepsynthesis disclosed in U.S. Patent Application Publication 2008/0114033A1 to a larger scale synthesis, such as production in a pilot plant oron a manufacturing scale. One difficulty is that the HofmannRearrangement step was not readily adaptable to commercial scalesynthesis. Further, there is a continuing need to find a process thatprovides higher yields in order to improve manufacturing economicsand/or reduce waste. Preferably, a new process will employ lessexpensive starting materials.

Desired is a process that is suitable for preparing larger quantities ofthe pyridinone compound of Formula (I) than is typically prepared bylaboratory scale processes. Also desired is a process that provideshigher yields of the pyridinone compound of Formula (I) than thepreviously disclosed processes.

The present invention is directed to one or both of these, as well asother important aspects.

SUMMARY OF THE INVENTION

Described herein is a process for preparing a compound of Formula (I):

comprising the steps of:(a) reacting a carboxylic acid compound of Formula (III):

or an activated carboxylic acid compound thereof, and an anilinecompound of Formula (II):

wherein PAm is a protected amine group, to provide a compound of Formula(IV):

and(b) converting said protected amine group attached to said compound ofFormula (IV) to an amine group to provide said compound of Formula (I);wherein: G is

each R¹ is independently alkyl, haloalkyl, halogen, or CN;each R² is independently alkyl, haloalkyl, halogen, or CN;R³ is phenyl substituted with alkyl, haloalkyl, halogen, or CN;each R⁴ is independently alkyl, haloalkyl, alkoxy, halogen, or CN;m is zero, 1, 2, 3, or 4;n is zero, 1, 2, or 3;p is zero, 1 or 2; andq is zero, 1, 2, or 3.

Also disclosed are compounds useful in the hereinabove process andprocesses to prepare these compounds.

DETAILED DESCRIPTION

Listed below are definitions of various terms used to describe thepresent invention. These definitions apply to the terms as they are usedthroughout the specification (unless they are otherwise limited inspecific instances) either individually or as part of a larger group.

The term “alkyl” and “alk” refer to a straight or branched chain alkane(hydrocarbon) radical containing from 1 to 12 carbon atoms, preferablyfrom 1 to 6 carbon atoms, and more preferably from 1 to 4 carbon atoms.Exemplary “alkyl” and/or “alk” groups include, but are not limited to,for example, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, pentyl,hexyl, isohexyl, heptyl, octyl, nonyl, decyl, and dodecyl.

The term “lower alkyl” refers to an “alkyl” and/or “alk” groupcontaining from 1 to 4 carbon atoms and preferably from 1 to 2 carbonatoms. When a subscript is used with reference to an alkyl or othergroup, the subscript refers to the number of carbon atoms the group maycontain. For example, the term “C₀-C₄alkyl” includes a bond and an alkylgroup containing 1 to 4 carbon atoms, and the term “C₁-C₄alkyl” refersto alkyl groups containing 1 to 4 carbon atoms. Exemplary lower alkylgroups include, but are not limited to, for example, methyl, ethyl,propyl, isopropyl, n-butyl, t-butyl, and isobutyl.

The term “halogen” and “halo” refer to fluorine, chlorine, bromine, andiodine.

The term “haloalkyl” refers to an alkyl group substituted at one or morepositions with halo substituents. Exemplary haloalkyl groups include,but are not limited to, haloalkyls having a single halo substituent suchas —CH₂F, —CH₂Cl, and —CH₂Br, and haloalkyls having multiple halosubstituents such as —CHF₂, —CF₃, —CHCl₂, and —CCl₃.

The term “cyano” refers to —CN.

The term “amine” refers to —NH₂.

The term “carboxylic acid” refers to —C(O)OH, which may be depicted as:

The term “alkoxy” refers to —O-alkyl. Examples of alkoxy groups include,but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, andt-butoxy.

The term “amide linkage” refers to —NHC(O)—, which may be depicted as:

The pyridinone compound of Formula (V) may exist in the enol formrepresented by the formula below:

As used herein, the terms “compound of Formula (V)” and “compound ofFormula (V-enol)” refer to the compound of Formula (V) in the keto form,the enol form, or any mixture comprising the keto and enol forms.

One aspect of the present invention relates to a process for preparingthe compound of Formula (I) in which the compound of Formula (I)comprises an amide linkage and a pyridyl group substituted with an amine

The amide linkage in the compound of Formula (I) can be prepared byreacting the carboxylic acid compound of Formula (III) or an activatedcarboxylic acid compound thereof, with the aniline compound of Formula(II), wherein the aniline compound of Formula (II) comprises a pyridylgroup having a protected amine group (PAm). The amide linkage is formedby reaction of the amine group attached to the phenyl ring (the anilinegroup of the compound of Formula (II)) and the carboxylic acid group ofthe compound of Formula (III) or an activated carboxylic acid groupthereof. The protected amine group minimizes and/or eliminates competingside reactions between the amine functionality attached to the pyridylgroup of the compound of Formula (II) and the carboxylic acid compoundof Formula (III) or an activated carboxylic acid compound thereof.

After formation of the amide linkage, the protected amine group (PAm)attached to the compound of Formula (IV) is converted to an amine groupto provide the compound of Formula (I):

The protected amine group (PAm) comprises a nitrogen atom that is bondeddirectly to the pyridyl ring and further comprises one or two blockinggroups attached to the nitrogen atom. The blocking groups minimize oreliminate reactions of the nitrogen atom bonded to the pyridyl ringduring the formation of the amide linkage between the aniline compoundand the carboxylic acid compound. The protected amine group isnonreactive or substantially nonreactive during the formation of theamide linkage. After the formation of the amide linkage, the blockinggroups are removed to provide the amine substituted pyridyl group of thecompound of Formula (I). The protected amine group expressly excludesgroups in which the nitrogen atom is not directly attached to thepyridal ring, such as —C(O)NH₂.

Various protected amine groups may be employed in the process of thepresent invention. Examples of suitable protected amine groups include,but are not limited to, imines, alkylamines, arylamines, carbamates,amides, imides, benzylamines, allylamines, silylamines, phosphonamides,sulfonamides, and triazinanones.

TABLE 1 Protected Amine Groups Protected as General formula ExamplesImine —N═C(R)₂ R = H, alkyl, aryl Benzophenone imine (R = Ph) Alkylamine—NH—R or N(R)₂ R = alkyl, aryl arylamine t-Butylamine (R = t-butyl)Benzyl (R = CH₂Ph) p-Methoxybenzyl (R = CH₂-anisole) Carbamate —NHCOORor R = H, alkyl, aryl —N(COOR)₂ BOC (R = t-butyl) Ethylcarbamate (R =Et) Amide —NHCOR R = H, alkyl, aryl Pivolate (R = t-butyl) Triflate (R =COCF₃) Formamide (R = H) Imide —N(COR)₂ R = H, alkyl, aryl PhthalimideBenzylamine or —NH—CH₂R or R = vinyl, aryl Allylamine —N(CH₂R)₂Benzhydryl (R = Ph) Allyl and diallyl (R = CH═CH₂) Silylamine —NHSiR₃ orR = alkyl —N(SiR₃)₂ HMDS (R = Me) Phosphonamide —NHPO(R)₂ R = alkoxy (R= OEt) Sulfonamide —NHSO₂R (R = CH₂CH₂SiMe₃) Nosyl (R = p-nitrophenyl)Triazinanones

R = Benzyl, alkyl

Preferred protected amine groups include imines, amides, carbamates,imides, sulfonamides, silylamines, benzylamines, allylamines,phosphonamides, and triazinanones. More preferred protected amine groupsinclude imines, amides, carbamates, imides, and sulfonamides.

Step I: Formation of Amide Linkage

Various synthetic routes can be employed to form the amide linkage bythe reaction of the carboxylic acid compound of Formula (III) and theaniline compound of Formula (II). One route is the reaction of thecarboxylic acid compound of Formula (III) and the aniline compound ofFormula (II), optionally in the presence of a suitable catalyst, such asan acid or a base catalyst. Another route is the reaction of anactivated carboxylic acid compound of Formula (III) and the anilinecompound of Formula (II). The activated carboxylic acid compound ofFormula (III) can be prepared by contacting the carboxylic acid compoundof Formula (III) with an activating agent to provide the activatedcarboxylic acid compound of Formula (III), prior to reaction with theaniline compound of Formula (II). As used herein, the step of reacting acarboxylic acid compound of Formula (III) and an aniline compound ofFormula (II) includes both the reaction between the carboxylic acidcompound of Formula (III) and/or the activated carboxylic acid compoundthereof, and the aniline compound of Formula (II).

In one embodiment, the process of the present invention comprisespreparing the compound of Formula (I) by a) reacting an activatedcarboxylic acid compound of Formula (III) and an aniline compound ofFormula (II) to provide a compound of Formula (IV); and b) convertingthe protected amine group attached to said compound of Formula (IV) toan amine group to provide said compound of Formula (I). For example, anactivated carboxylic acid compound of Formula (IIIc), such as an acidhalide compound of Formula (IIIc), can be reacted with the anilinecompound of Formula (II) to provide the compound of Formula (IV).

wherein X is an activating group such as, for example, chlorine. Methodsfor activating carboxylic acid groups to prepare amide linkages,including activating agents, solvents, and reaction conditions, aredescribed in Han, S.-Y. et al., Tetrahedron 60 (2004) 2447-2467.

The activated carboxylic acid compounds of Formula (IIIc) can beprepared by contacting the carboxylic acid compound of Formula (III)with various adjuvants including, but not limited to, acid halidesincluding acid chlorides such as oxalyl chloride (COCl)₂,sulfonylchloride (SO₂Cl), Vilsmeier reagent(N-chloromethylene-N,N-dimethyl ammonium chloride), phosphorylchloride(POCl₃), PO(OEt)₂Cl, and pivaloylchloride (t-BuCOCl); uronium salts suchas O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU); dicarbodiimides such asdicyclohexylcarbodiimide andN-(3-dimethylaminopropyl)-N′ethyldicarbodiimide, with or without1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt);2-hydroxypyridine-1-oxide;4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride(DMTMM); chloroformates (general formula ROCOCl) such astert-butylchloroformate, iso-butylchloroformate, andisopropylchloroformate; propylphosphonic anhydride; diethylchlorophosphate; Mitsunobu reagents including diethylazodicarboxylateand triphenylphosphine; and trimethylsilyl-isothiocyanate (TMS-ITC).Preferred reagents include dicyclohexylcarbodiimide,N-(3-dimethylaminopropyl)-N′-ethyldicarbodiimide, Vilsmeier reagent,oxalyl chloride, thionyl chloride, propylphosphonic anhydride, diethylchlorophosphate, pivaloyl chloride, chloroformates including tert-butylchloroformate, iso-butylchloroformate, isopropylchloroformate,trimethylsilyl-isothiocyanate, and Mitsunobu reagents(diethylazodicarboxylate and triphenylphosphine). More preferredreagents include Vilsmeier reagents, oxalyl chloride, and thionylchloride.

The reaction of the carboxylic acid compound of Formula (III) or theactivated carboxylic acid compound of Formula (IIIc) with the anilinecompound of Formula (II) can be conducted in the presence of varioussynthesis adjuvants, including, for example, organic bases such astriethyl amine, potassium tert-butoxide, sodium 2-ethylhexanoate, andN,N-diisopropylethylamine (DIPEA); and inorganic bases such as sodiumcarbonate and cesium carbonate. Other suitable adjuvants includeacylation catalysts such as 4-dimethylaminopyridine (DMAP),1-hydroxybenzotriazole, 2-pyridone, 1,4-diazabicyclo[2.2.2]octane(DABCO), 1,8-diazabicylco[5.4.0]undec-7-ene (DBU), and 2,6-lutidine.Preferred synthesis adjuvants include organic bases such as triethylamine, potassium tert-butoxide, and sodium 2-ethylhexanoate; andacylation catalysts such as 2-pyridone, 4-dimethylaminopyridine,1-hydroxybenzotriazole, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicylco[5.4.0]undec-7-ene, and 2,6-lutidine. Most preferredsynthesis adjuvants include sodium 2-ethylhexanoate.

The reaction between a carboxylic acid compound of Formula (III) or anactivated carboxylic acid compound Formula (IIIc), and the anilinecompound of Formula (II) can be conducted in various solvents ormixtures thereof. Examples of suitable solvents include, but are notlimited to, polar aprotic solvents such as dimethyl formamide, dimethylsulfoxide, and N-methylpyrrolidinone; etheral solvents suchtetrahydrofuran, 2-methyl tetrahydrofuran, methyl t-butyl ether, anddiethoxymethane; hydrocarbons such as benzene, toluene, hexanes, andheptane; halogenated solvents such as dichloromethane and1,2-dichloroethane; acetates such as ethyl acetate, isopropyl acetate,and butyl acetate, and other solvents such as acetonitrile, methyl vinylketone, N,N-dimethylacetamide; and mixtures thereof. Preferred solventsinclude etheral solvents such tetrahydrofuran, 2-methyl tetrahydrofuran,and diethoxymethane; hydrocarbons such as toluene and heptane; andhalogenated solvents such as dichloromethane and 1,2-dichloroethane.More preferred solvents include halogenated solvents such asdichloromethane and 1,2-dichloroethane.

Suitable reaction temperatures for the reaction between the carboxylicacid compound of Formula (III) or the activated carboxylic acid compoundthereof, and the aniline compound of Formula (II) include temperaturesin the range of from about −50° C. to about 150° C., preferably in therange of from −25° C. to about 100° C., and more preferably in the rangeof from 0° C. to 50° C.

In one embodiment, the activated carboxylic acid compound of Formula(IIIa) is prepared by reacting the carboxylic acid compound of Formula(III) and oxalyl chloride in a halogenated solvent, such asdichloromethane, and/or dimethyl formamide at a temperature in the rangeof from −20° C. to −40° C.

Step II: Removal of Protecting Group to Generate Amine

After formation of the compound of Formula (IV), the protected aminegroup attached to the pyridyl group of said compound is converted to anamine group to provide the compound of Formula (I). Various methods maybe employed to convert the protected amine group to the amine groupwithout affecting the amide linkage. Examples of suitable methodsinclude:

a) Treatment with organic, inorganic, or Lewis acids in the presence ofwater. Suitable acids include, for example, formic acid, acetic acid,methanesulfonic acid, trifluoroacetic acid, citric acid, hydrochloricacid, sulfuric acid phosphoric acid, magnesium triflate, and lithiumbromide.b) Treatment with organic, inorganic, or Lewis acids without theaddition of water. Suitable acids include, for example, formic acid,acetic acid, magnesium triflate, and lithium bromide.c) Treatment with organic or inorganic bases, including, for example,carbonates (M_(m)CO₃)n) such as K₂CO₃, Na₂CO₃, and Cs₂CO₃; hydroxides(M_(m)(OH)_(n)) such as KOH, NaOH, and LiOH; alcoholates (M_(m)(OR)_(n))such as NaOCH₃, KO(t-butyl), and Na(O-ethyl); phosphates(M_(m)(PO₄)_(n)) such as K₂HPO₄ and K₃PO₄; and amines such astriethylamine, N,N-diisopropylethylamine, N-methyl morpholine,1,4-diazabicyclo[2.2.2]octane (DABCO), and1,8-diazabicylco[5.4.0]undec-7-ene.d) Treatment by heating in the presence of water.e) Treatment with fluoride.f) Treatment with oxidants such as ceric ammonium nitrate (CAN) and2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

Suitable solvents for conversion of the protected amine group include,for example, polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidinone; etheral solvents such astetrahydrofuran, 2-methyl tetrahydrofuran, methyl t-butyl ether, anddiethoxymethane; hydrocarbons such as toluene, heptane, benzene, andhexanes; halogenated solvents such as dichloromethane and1,2-dichloroethane; acetates such as ethyl acetate, isopropyl acetate,and butyl acetate; alcohols such as methanol, ethanol, and isopropanol;and other solvents such as acetonitrile, methyl vinyl ketone, andN,N-dimethylacetamide; and mixtures thereof. Preferred solvents includetetrahydrofuran, 2-methyl tetrahydrofuran, methyl t-butyl ether,toluene, N-methylpyrrolidinone, dimethylformamide,N,N-dimethylacetamide, and ethanol.

Suitable reaction temperatures for converting a protected amine group toan amine group include temperatures in the range of from about −78° C.to about 200° C., preferably in the range of from −25° C. to about 150°C., and more preferably in the range of from 0° C. to 100° C.

The compound of Formula (I) and the compound of Formula (IV) can beisolated and/or purified by various methods known in the art. Suitablemethods include chromatography, crystallization, filtration, anddistillation.

In one embodiment, the process for preparing a compound of Formula (I)employs the aniline compound of Formula (II) and/or the compound ofFormula (IV) wherein the protected amine group, PAm, is —NH—R^(b),—NHC(O)OR^(a), —NHC(═O)R^(a), —NH(CH₂R^(c)), —NHSi(R^(d))₃,—NH(PO(OR^(d))₂), —NHSO₂R^(e), —N(R^(b))₂, —N(C(O)OR^(a))₂,—N(C(O)R^(a))₂, —N(CH₂R^(c))₂, —N(Si(R^(d))₃)₂, —N═C(R^(a))₂, or

wherein: each R^(a) is independently H, alkyl, haloalkyl, benzyl, and/oraryl; each R^(b) is independently alkyl, haloalkyl, benzyl,methoxybenzyl, and/or aryl; each R^(c) is independently allyl or alkoxy;each R^(d) is independently alkyl; R^(e) is alkyl, alkyl substitutedwith —Si(alkyl)₃, phenyl, or nitrophenyl; and each R^(f) isindependently alkyl or benzyl. Preferably, PAm is an imine, imide,carbamate, amide, or sulfonamide. More preferably, PAm is an imine orimide.

In one embodiment, the process for preparing a compound of Formula (I)is employed to prepare compounds of Formula (I) in which R¹ is halogenand m is zero, 1, or 2. Preferably, m is 1. Preferably, R¹ is F or Cl,and more preferably F. More preferably, R¹ is F and m is 1.

In one embodiment, the process for preparing a compound of Formula (I)is employed to prepare compounds of Formula (I) in which R² is halogenand n is zero, 1, or 2. Preferably, n is 1. Preferably, R² is F or Cl,and more preferably F. More preferably, R² is F and n is 1.

In one embodiment, the process for preparing a compound of Formula (I)is employed to prepare compounds of Formula (I) in which R³ is phenylsubstituted with C₁-C₄ alkyl, C₁-C₃ halo alkyl, halogen, or CN;preferably, R³ is methyl, ethyl, trifluoromethyl, pentafluoroethyl,halogen, or CN; and more preferably, R³ is methyl, trifluoromethyl, F,Cl, or CN.

In one embodiment, the process for preparing a compound of Formula (I)is employed to prepare compounds of Formula (I) in which R³ is phenylsubstituted with halogen; more preferably, R³ is phenyl substituted withF or Cl; and still more preferably, R³ is a fluorophenyl, including, forexample, 4-fluorophenyl.

In one embodiment, the process for preparing a compound of Formula (I)is employed to prepare the pyridinone compoundN-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,which has the structure represented by Formula (Ia)

or the pyridinone compoundN-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide,which has the structure represented by Formula (Ib)

U.S. Patent Application Publication 2008/0114033 A1 discloses theCompound of Formula (Ia) and is incorporated herein in its entirety.U.S. Provisional Patent Application 61/022,848 discloses the Compound ofFormula (Ib) and prodrugs thereof, and is incorporated herein in itsentirety. The present application claims priority to U.S. ProvisionalPatent application 61/022,848. These compounds are Met kinasesinhibitors and are useful in the treatment of cancers, such as, forexample, bladder cancer, breast cancer, colorectal cancer, gastriccancer, head and neck cancer, kidney cancer, liver cancer, lung cancer,ovarian cancer, pancreas/gall bladder cancer, prostate cancer, thyroidcancer, osteosarcoma, rhabdomyosarcoma, malignant fibrous histiocytoma(MFH), fibrosarcoma, glioblastomas/astrocytomas, melanoma, andmesothelioma.

In one embodiment, a process is provided for preparingN-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide,the compound of Formula (Ia)

In this embodiment, the process comprises the steps of: (a) reacting ananiline compound of Formula (IIb):

and an carboxylic acid compound of Formula (IIIa):

or an activated carboxylic acid compound thereof, to provide a compoundof Formula (IVa):

wherein PAm is a protected amine group; and(b) converting said protected amine group attached to said compound ofFormula (IVa) to an amine group to provide said compound of Formula(Ia).In one embodiment, a process is provided for preparing a compound ofFormula (Ib):

In this embodiment, the process comprising the steps of: a) reacting ananiline compound of Formula (IIb):

with an carboxylic acid compound of Formula (IIb):

or an activated carboxylic acid compound thereof, to provide a compoundof Formula (IVb):

wherein PAm is a protected amine group; andb) converting said protected amine group attached to said compound ofFormula (IVb) to an amine group to provide said compound of Formula(Ib).

The compound of Formula (Ib) may be provided as a prodrug, as disclosedin U.S. Provisional Application 61/022,848.

One embodiment provides a compound of Formula (VIIIa) having thestructure:

wherein PAm is defined hereinabove. One example of a compound of thisembodiment is 3-chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-one,which has the structure of Formula (3A):

In another embodiment, a process is provided comprising the step ofreacting 2,3-dichloropyridine and benzophenone imine to provide3-chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-one.

In the process of this embodiment, various solvents, synthesisadjuvants, and reaction conditions can be employed. Examples of suitablesolvents include, but are not limited to, polar aprotic solvents such asdimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidinone;etheral solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, anddiethoxymethane; hydrocarbons such as toluene, heptane, benzene, andhexanes; halogenated solvents such dichloromethane and1,2-dichloroethane; acetates such as ethyl acetate, isopropyl acetate,and butyl acetate; other solvents such as acetonitrile and methyl vinylketone; or mixtures thereof. The reaction can be conducted in thepresence of various synthesis adjuvants such as catalysts, bases, and/orligands. Examples of suitable catalysts include, but are not limited to,palladium catalysts such as palladium acetate andtetrakis(triphenylphosphine)palladium; copper catalysts such as copper(I) halides and copper (II) trifluoromethanesulfonate; and nickelcatalysts such as Bis(1,5-cyclooctadiene)nickel (0); which can bepresent in range of from 0.0001 to 1.5 equivalents. Examples of suitableligands include, but are not limited to, phosphine ligands such as2,2′-bis(diphenylphosphino)-1,1′-binaphthylene, P(alkyl)₂(phenyl),P(alkyl)(phenyl)₂, and P(phenyl)₃; and nitrogen heterocycles such asimidazole and hydroxy pyridine, which can be present in the range offrom 0.0001 to 1.5 equivalents. Examples of suitable bases include, butare not limited, inorganic bases such as sodium carbonate, and cesiumcarbonate; and organic bases such as triethylamine and potassiumbutoxide; which can be present in the range of from 1 to 10 equivalents.Preferably, the reaction of this embodiment is conducted in at least onesolvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran,diethoxymethane, toluene, and/or heptane; and more preferably,tetrahydrofuran, 2-methyl tetrahydrofuran, and/or diethoxymethane.Preferably, the reaction of this embodiment is conducted in the presenceof at least base selected from sodium carbonate and/or cesium carbonate.Preferably, the reaction of this embodiment is conducted in the presenceof at least one palladium catalyst, for example, palladium acetateand/or tetrakis(triphenylphosphine)palladium. Preferably, the reactionof this embodiment is conducted in the presence of at least onephosphine ligand selected from2,2′-bis(diphenylphosphino)-1,1′-binaphthylene, P(alkyl)₂(phenyl),P(alkyl)(phenyl)₂, and P(phenyl)₃. For example, the reaction of thisembodiment can be conducted in the presence of cesium carbonate,palladium acetate, and 2,2′-bis(diphenylphosphino)-1,1′-binaphthylene inat least one solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, and/or diethoxymethane. In the present embodiment, thereaction to prepare 3-chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-onecan be conducted at temperatures in the range of from about −78° C. toabout 200° C., preferably in the range of from −25° C. to about 150° C.,and more preferably in the range of from 0° C. to 100° C. The reactionproduct can be separated and purified by methods known in the art.

One embodiment provides a compound of Formula (Vb) having the structure:

wherein PAm is defined hereinabove. One example of a compound of thisembodiment is 3-chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-one,which has the structure of Formula (3B):

One embodiment provides a compound of Formula (VIIa)

wherein each R¹ is independently alkyl, haloalkyl, halogen, or CN; eachR² is independently alkyl, haloalkyl, halogen, or CN; m is zero, 1, 2,3, or 4; n is zero, 1, 2, or 3; and PAm is a protected amine group.Preferably, R¹ is halogen, m is 1, R² is halogen, and n is 1.Preferably, PAm is an imine, imide, carbamate, amide, or sulfonamide.More preferably, PAm is an imine or imide.

In one embodiment, provided is a compound of Formula (VIIb):

wherein PAm is defined hereinabove. Preferably, PAm is an imine, imide,carbamate, amide, or sulfonamide. More preferably, PAm is an imine orimide.

One embodiment provides an aniline compound of Formula (II)

or a salt thereof; and/or an aniline compound of Formula (IIa)

or a salt thereof, wherein each R¹ is independently alkyl, haloalkyl,halogen, or CN; each R² is independently alkyl, haloalkyl, halogen, orCN; m is zero, 1, 2, 3, or 4; n is zero, 1, 2, or 3; and PAm is aprotected amine group. Preferably, R¹ is halogen, m is 1, R² is halogen,and n is 1. Preferably, PAm is an imine, imide, carbamate, amide, orsulfonamide. More preferably, PAm is an imine or imide.

In one embodiment, provided is the compound of Formula (IIc) or a saltthereof.

wherein PAm is defined hereinabove. Preferably, PAm is an imine, imide,carbamate, amide, or sulfonamide. More preferably, PAm is an imine orimide.

Preparation of Aniline Compounds of Formula (II)

The following reaction scheme shows various general synthetic routes forpreparing the compound of Formula (VIIb), which is useful as a precursorto the compound of Formula (IIc).

In one embodiment, a process is provided for preparing a compound ofFormula (V), comprising the step of oxidizing a compound of Formula(VIII).

The compound of Formula (VII) converted to the compound of Formula (V)by deprotonation, followed by direct oxidation; or alternatively, bydeprotonation, followed by boralation, and then oxidation. For example,the process of this embodiment can be employed to prepared3-chloro-2-(diphenylmethyleneamino) pyridin-4(1H)-one by oxidizing3-chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-one.

Various solvents, synthesis adjuvants, and reaction conditions can beemployed in the process of this embodiment. Examples of suitablesolvents include, but are not limited to, polar aprotic solvents such asdimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidinone;etheral solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, anddiethoxymethane; hydrocarbons such as toluene, heptane, benzene, andhexanes; and halogenated solvents such dichloromethane and1,2-dichloroethane, or mixtures thereof. The reaction can be conductedin the presence of various synthesis adjuvants including oxidants suchas hydrogen peroxide, sodium percarbonate, potassium peroxymonosulfate(Oxone™ compound), and sodium tetrafluoroborate; peroxides such ast-butyl hydrogen peroxide and m-chloroperoxybenzoic acid;trialkoxyborates; and/or lithium amides such as lithiumdiisopropylamide. Suitable amounts of peroxide, trialkoxyborates, andlithium amide include 1 to 4 equivalents each. Preferred solventsinclude tetrahydrofuran, 2-methyl tetrahydrofuran, diethoxymethane,toluene, and heptane, or a mixture thereof. Preferred oxidants includehydrogen peroxide, sodium percarbonate, and potassium peroxymonosulfate.For example, the process of this embodiment can be employed to prepare3-chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-one by reacting3-chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-one in the presence of1-3 equivalents of lithium diisopropylamide, 1-4 equivalents oftriisopropoxyborate, and an oxidizing agent selected from sodiumpercarbonate and/or potassium peroxymonosulfate in a solvent selectedfrom tetrahydrofuran, 2-methyl tetrahydrofuran, diethoxymethane,toluene, and heptane, or a mixture thereof.

In another embodiment, a process is provided for preparing the compoundof Formula (VIIb), comprising the step of reacting a compound of Formula(Vb) with 1,2-difluoro-4-nitrobenzene.

In the process of this embodiment, various solvents, synthesisadjuvants, and reaction conditions can be employed. Examples of suitablesolvents include, but are not limited to, polar aprotic solvents such asdimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidinone;etheral solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, anddiethoxymethane; hydrocarbons such as toluene, heptane, benzene, andhexanes; halogenated solvents such dichloromethane and1,2-dichloroethane; acetates such as ethyl acetate, isopropyl acetate,and butyl acetate; other solvents such as acetonitrile and methyl vinylketone; or mixtures thereof. The reaction can be conducted in thepresence of various synthesis adjuvants including bases. Examples ofsuitable bases include, but are not limited, inorganic bases such assodium carbonate, lithium carbonate, and cesium carbonate; and organicbases such as triethylamine and potassium butoxide. The process of thepresent embodiment can be conducted at temperatures in the range of fromabout −78° C. to about 200° C., preferably in the range of from −25° C.to about 150° C., and more preferably in the range of from 0° C. to 100°C. The reaction product can be separated and purified by methods knownin the art. Preferably, the reaction of this embodiment is conducted ina solvent selected from dimethylformamide, dimethyl sulfoxide, andN-methylpyrrolidinone, or mixtures thereof. Preferably, the reaction ofthis embodiment is conducted in the presence of at least inorganic base,such as sodium carbonate, lithium carbonate, and/or cesium carbonate.For example, the process of the present embodiment can be conducted inthe presence of lithium carbonate and/or cesium carbonate in a solventselected from dimethyl formamide, N-methylpyrrolidinone, and mixturesthereof.

In another embodiment, a process is provided for preparing an anilinecompound of Formula (II), comprising the step of converting a compoundof Formula (VII) to a compound of Formula (II)

For example, the process of this embodiment can be used to prepare theaniline compound of Formula (IIb) from the compound of Formula (VIIb).

In the process of this embodiment, various solvents, synthesisadjuvants, and reaction conditions can be employed. Examples of suitablesolvents include, but are not limited to, polar aprotic solvents such asdimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidinone;etheral solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, anddiethoxymethane; alcohols such as ethanol and isopropanol; hydrocarbonssuch as toluene, heptane, benzene, and hexanes; halogenated solventssuch dichloromethane and 1,2-dichloroethane; acetates such as ethylacetate, isopropyl acetate, and butyl acetate; other solvents such asacetonitrile and methyl vinyl ketone; or mixtures thereof. The reactioncan be conducted in the presence of various synthesis adjuvantsincluding, but not limited to, bases, reductants, transition metals,catalysts, and a hydrogen source. Examples of suitable reductantsinclude, but are not limited to, sodium dithionite sodium sulfide,ammonium sulfide, FeSO₄, and sodium borohydride. Examples of suitabletransition metals include, but are not limited to, Fe, Pd, Rh, and Ir.Suitable hydrogen sources include hydrogen gas and formic acid. Examplesof suitable bases include, but are not limited, inorganic bases such assodium carbonate, lithium carbonate, and cesium carbonate; and organicbases such as triethylamine and potassium butoxide. The process of thepresent embodiment can be conducted at temperatures in the range of fromabout −78° C. to about 200° C., preferably in the range of from −25° C.to about 150° C., and more preferably in the range of from 0° C. to 100°C. The reaction product, the compound of Formula (II), can be separatedand purified by methods known in the art. Preferably, the reaction ofthis embodiment is conducted in a solvent selected fromdimethylformamide, dimethyl sulfoxide, N-methylpyrrolidinone,tetrahydrofuran, 2-methyl tetrahydrofuran, diethoxymethane, ethanol,isopropanol, or mixtures thereof. Preferably, the reaction of thisembodiment is conducted in the presence of a reductant selected fromsodium sulfide, ammonium sulfide, and FeSO₄. Preferably, the reaction ofthis embodiment is conducted in the present of a transition metalselected from Pd or Ni. For example, the process of the presentembodiment can be conducted in the presence of ammonium sulfide, nickelsuch as Raney-Ni, a hydrogen source, and base in a solvent selected fromisopropanol, ethanol, tetrahydrofuran, 2-methyl tetrahydrofuran, andmixtures thereof.

In one embodiment, a process is provided for preparing the compound ofFormula (VIIb), comprising the steps of reacting2,3-dichloro-1,4-dihydropyridin-4-ol and 1,2-difluoro-4-nitrobenzene toprovide the compound of Formula (IX),

and converting the compound of Formula (IX) to the compound of Formula(II). Suitable solvents, synthesis adjuvants, and reaction conditionsare disclosed hereinabove.

In one embodiment, a process is provided for preparing the anilinecompound of Formula (II) comprising the steps of: a) reacting apyridinone compound of Formula (V):

with a 4-halo-nitrobenzene compound of Formula (VI):

wherein X is a halogen and PAm is a protected amine group, to provide acompound of Formula (VII):

and b) converting said compound of Formula (VII) to the aniline compoundof Formula (II):

Preferably, in the process of this embodiment, preferably X is F or Cl.Solvents, synthesis adjuvants, and reaction conditions are disclosedhereinabove.

In one embodiment, a process is provided for preparing the anilinecompound of Formula (IIa) comprising the steps of: a) reacting apyridinone compound of Formula (Va):

with a 4-halo-nitrobenzene compound of Formula (VI), wherein PAm is aprotected amine group, to provide a compound of Formula (VIIa):

and b) converting said compound of Formula (VIIa) to the anilinecompound of Formula (IIa):

Preferably, in the process of this embodiment, preferably X is F or Cl.

In one embodiment, a process is provided for preparing the anilinecompound of Formula (IIb) comprising the steps of: a) reacting apyridinone compound of Formula (Vb):

with a 4-halo-nitrobenzene compound of Formula (VI), wherein PAm is aprotected amine group, to provide a compound of Formula (VIIb):

and b) converting said compound of Formula (VIIb) to the anilinecompound of Formula (IIb):

Suitable solvents, synthesis adjuvants, and reaction conditions for step(a) and step (b) are disclosed hereinabove and in the Examples.

EXAMPLES

ABBREVIATIONS BuOAc butyl acetate DCM dichloromethane DMFdimethylformamide EtOH ethanol Et ethyl EtOAc ethyl acetate HPLC highpressure liquid chromatography hrs hours LDA lithium diisopropylamineLOD loss on drying Me methyl MeCN acetonitrile MeOH methanol MeTHF2-methyltetrahydrofuran min minutes MTBE methyl tert-butyl ether NaOEtsodium ethoxylate Ph phenyl rac-BINAP2,2′-bis(diphenylphosphino)-1,1′-binaphthylene THF tetrahydrofuran

Example 1 Preparation ofN-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Step 1. Preparation of3-Chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-one

To a reactor, 35 L of MeTHF and 5.0 kg of 2,3 dichloropyridine werecharged and agitation started. Next, 0.155 kg of palladium acetate, 0.64kg of rac-BINAP and 23.0 kg of cesium carbonate were added to the abovereaction mixture, followed by the addition of 6.2 kg of benzophenoneimine, while maintaining the temperature between 25 and 28° C. Thereaction mixture was heated to 80-85° C. and stirred for 24 hours. Afterthe reaction was complete, the reaction mixture was cooled to 25-30° C.The precipitate was filtered off and the solids were washed twice with20 L of THF. The filtrate was charged back to the equipment andconcentrated to minimum volume.

In a separate reactor, 35 L of THF and 10 L of diisopropylamine werecharged under nitrogen atmosphere. The mixture was cooled to −20 to −25°C. and 13.3 kg of n-butyllithium were added over a period of 30 min toprepare a lithium diisopropylamide (LDA) solution. Then the mixture wascooled to −75 to −80° C. and the concentrated filtrate, dissolved in 25L of THF, was slowly dosed to the LDA solution while maintaining thetemperature between −75 to −80° C. The reaction mixture was stirred for2 hours. Afterwards 10.0 L of triisopropylborate were added and thetemperature was slowly raised to 20° C. The reaction mixture was stirredfor 2 hours at 20° C. Next, the reaction mixture was cooled to 0° C. and50 L of water were added to the reaction mixture, followed by 30 kg ofOXONE™ compound (potassium peroxymonosulfate) while maintaining thetemperature between 20-25° C. The reaction mixture was stirred for onehour until the reaction was complete. Then, 270 L of water were addedand the reaction mixture was stirred for 12 hours. Next, the slurry wasfiltered and the solids washed with 40 L of water. The solids werecharged back to the reactor and re-slurried in 25 L of ethyl acetate for30 minutes. After filtration, the solids were washed with 10 L ofpetroleum ether. The resulting material was removed from the filter anddried for 12 hours at 35-40° C. Yield of3-Chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-one: off-white solid(6.1 kg; 60% yield).

Step 2. Preparation of3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine

To a reactor was added 24 g of 3-chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-one, DMF (100 mL), cesium carbonate (12.7 g; 0.5 eq) anddifluoronitrobenzene (9.3 mL; 1.1 eq). The reaction mixture was heatedto 95° C. and stirred for three hours. After the reaction was complete,the reaction mixture was poured onto crushed ice and the solids werefiltered off and washed with water. The crude solids were charged backto the reactor and dissolved in THF (200 mL). Methanol was added and themixture was distilled at a constant volume of 350 mL, until THF had beenazeotropically removed. Additional methanol (100 mL) was added and thesuspension was cooled to room temperature. The solids were filtered anddried under vacuum to yield3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine(23.3 g; 67% yield).

Step 3. Preparation of4-(4-Amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine

To a reactor was added 10 g of3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine,1.4 g of Ra-Nickel (type A-5001 from Johnson Matthay) and 100 mL ofMe-THF. The reactor was inerted by three nitrogen/hydrogen swings, thenpressurized to 25 psig with hydrogen. The reaction mixture was stirredunder 25 psig of hydrogen at 25° C. until the hydrogen uptake ceased(1.6 L consumed) and the reaction was judged complete by HPLC. BuOAc (50mL) was added to the reaction mixture and MeTHF was distilled off underatmospheric pressure until <1% of Me-THF were detected by GC.Maintaining a batch temperature of 90° C., heptane (50 mL) was addedover 20 min. The solution was then allowed to cool to room temperatureover 8 hrs. The solids were filtered off and the cake was washed with 50mL heptane. The solid was dried in a vacuum oven at 60° C. for 12 hr toafford4-(4-Amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine(8.88 g; 95% yield) as a light yellow crystalline solid.

Step 4. Preparation of (4E)-ethyl2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate

Acetic acid (0.43 kg), ethyl cyanoacetate (16 kg) and triethylorthoacetate (7.5 kg) were charged to a reactor equipped with adistillation head. The reaction mixture was heated to 110-115° C. untilthe EtOH was distilled from the reaction mixture. Additional triethylorthoacetate (4.8 kg) and acetic acid (0.43 kg) were charged and theEtOH distillation was continued. This procedure was repeated until <2%of ethyl cyanoacetate was detected in the reaction mixture by GC.Residual EtOH and triethyl orthoacetate were then removed applying highvacuum to the reaction mixture at 110-115° C. The reaction mass wascooled to 50° C. and N,N′-dimethyl formamide diethylacetal (25.3 kg),DMF and EtOH were added. The mixture was heated to 70° C. for 2 hrsuntil the reaction was judged complete by HPLC. After cooling to roomtemperature, DMF (5.6 L) and EtOH (200 proof, 16 L) were added. Themixture was heated to 40° C., until all solids were dissolved.Maintaining the temperature in the range of 35-40° C., water was added.The resulting slurry was cooled to 15-20° C. After 2 hrs, the solidswere filtered and the cake washed with 30 L of water, followed by 64 Lof petroleum ether. After drying under vacuum, (4E)-ethyl2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate (31.5 kg; 93%yield) was obtained as a brown solid.

Step 5. Preparation of Ethyl4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate

(4E)-Ethyl 2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate (20 kg)and acetic acid (126 L) were charged to a reactor and heated to 100° C.for 3 hrs until the reaction was complete as characterized by HPLC. Thereaction mass was cooled to 55° C. and acetic acid was removed by vacuumdistillation at 65-75° C. After distillation, the mixture was cooled toroom temperature and water (3 L) was added. The pH of the mixture wasadjusted to 8 by addition of 100 L of a 30% sodium carbonate solution.The solids were filtered off and washed with 10 L of water. The combinedaqueous layers were extracted three times with DCM (100 L). The combinedDCM layers were washed with brine, then dried over sodium sulfate andconcentrated to dryness. Ethyl acetate was added to the concentrate. Themixture was heated to 40° C. and then cooled to 25° C. The solids werefiltered off, washed with petroleum ether and dried at room temperaturefor 12 hrs to yield ethyl4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (10.3 kg; 58.5% yield).

Step 6. Preparation of Ethyl4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate

DMF (9 L) and cesium carbonate (3.1 kg) were charged under nitrogen to areactor and stirred for 10 min at room temperature. To this mixture, asolution of 8-hydroxyquinoline (0.275 kg) in DMF (1 L), copper iodide(0.27 kg) and 1-fluoro-4-iodobenzene (1.576 kg) were added undernitrogen. Then, ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate(1 kg) was added and the reaction mixture was heated to 100° C. for 20hrs under nitrogen. After completion of the reaction, the mixture wasfiltered through celite. To the filtrate, water (100 L) was added andthe mixture was extracted three times with DCM (25 L). The combined DCMlayers were washed two times with water (20 L), two times with 1.5 N HCl(5 L), and one time with brine (10 L), and then dried over sodiumsulfate and concentrated to dryness. Petroleum ether (5 L) was added tothe concentrate and the resulting slurry was stirred for 30 min. Thesolids were filtered and dried at room temperature in vacuum to give 1.1kg crude ethyl4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate.

Step 7. Preparation of Carboxylic Acid Compound:4-Ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid

At room temperature, 2.75 N HCl (7.7 L) was added to a solution of crudeethyl4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1.1kg) in EtOH (3.85 L). The mixture was heated for 10 hrs to 60-64° C.Next, the mixture was cooled to 50-54° C. and methanol was removed byvacuum distillation. The mixture was cooled to 20-25° C. and the pH wasadjusted to 8.0 to 8.5 by addition of 30% sodium carbonate solution (8.5L). The phases were separated and the aqueous layer was washed threetimes with DCM (4 L). Next, charcoal (0.7 kg) was charged to the aqueouslayer and the layer was filtered through a celite bed. To the filtratewas added 1.5 N HCl until the pH had reached 2.0. The resulted slurrywas stirred for 20 min at room temperature. The solids were filteredoff, washed with water (15 L) and dried under vacuum at 50-55° C. untilthe loss on drying was less than 5 wt %. The crude product was suspendedin ethyl acetate (5 L) and slurried for 15 min at 40° C. After coolingto room temperature, the solids were filtered off, washed with ethylacetate (1 L) and dried at 40-45° C. under vacuum for 10 hrs to yield4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid(0.76 kg; 58% yield for Steps 6 and 7).

Step 8. Preparation ofN-(4-(3-chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

4-Ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid(1.20 equiv; 79.62 g), DCM (500.00 mL), and oxalyl chloride (23.88 mL)were added to a ChemGlass reactor at 25° C. DMF (20.00 mL) was addedover a period of approximately 20 min and the solution was allowed tostir at 20° C. for 30 min. The resulting acid chloride solution wascooled to −5° C.

Into a separate reactor,4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine(1.00 equiv; 100 g), DCM (500 mL), and sodium 2-ethylhexanoate (95.45 g)were charged and the resulting mixture (aniline solution) was cooled to−5° C.

The pre-cooled acid chloride solution was then added to the anilinesolution keeping the batch temperature below 5° C. The mixture wasallowed to stir at −5° C. for 3 hrs. After HPLC indicated the reactionwas complete, the reaction was quenched with methanol (29.06 mL). DCM(500 mL), aqueous sodium bicarbonate (500 mL), and water (500 mL) wereadded to the solution and the solution was allowed to warm to 25° C.with stirring. The layers were separated and the aqueous layer wasdiscarded. The DCM layer was washed with sodium bicarbonate (500 mL) andwater (500 mL). Diethoxymethane (total of 1500 mL) was added to the DCMlayer and DCM was distilled off until the batch temp reached 85° C.,keeping the volume constant at 10 L/kg. After GC analysis of thereaction mixture showed a diethoxymethane/DCM ratio of ≧99:1, thedistillation was stopped and the mixture was cooled to 25° C. Theprecipitate was filtered off and the cake was washed withdiethoxymethane (1.00 L), then methyl t-butyl ether (500 mL). The solidswas dried in a vacuum oven at 60° C. for 12 h to affordN-(4-(3-chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(0.97 equiv; 157.02 g; 96.90% yield) as a white solid.

Step 9. Preparation ofN-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

To a 250 mL vessel,N-(4-(3-chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(100.0 g, 147.7 mmoles, 1.0 eq) and methanol (900 mL) were charged. Thewhite slurry was cooled to 10° C. and concentrated HCl (16.3 g, 163.3mmoles, 1.105 eq) was added, maintaining the reaction temperature below10° C. The reaction mixture was held at 10° C. for approximately 2.5 h,until HPLC indicated ≦0.5 relative area percent of starting material.Water (500 mL) and MTBE (500 mL) were added and the reaction mixture waswarmed to 20° C. Next, 1N NaOH (184.08 g, 177.0 mL, 177 mmoles, 1.20eq), was added dropwise over 20 minutes while maintaining thetemperature between 15 and 20° C. The resulting slurry was cooled to 10°C. and aged for at least 10 minutes. The precipitate was filtered off,and the cake washed with water (2×350 mL), followed by a mixture ofmethanol: MTBE (10:90) (1×300 mL). Next, the cake was dried in a vacuumoven at 50-60° C. until LOD analysis indicated less than 1 wt % ofvolatiles.N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide:79.5 g (95% yield with 98.1 AP and 99.4 wt % potency). The resultingproduct (35.0 g) was subsequently re-crystallized from THF (367.2mL)/EtOH (200 proof, 244.8 mL)/n-heptane (350 mL) to obtainN-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(30.8 g) in 88% yield with >99.9 AP and 99.7 wt % potency.

Comparative Example 2 Preparation ofN-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamideby Process Disclosed in US 2008/0114033 A1

Step 1. Preparation of 3,4-Dichloropicolinic acid

As described previously by Marzi, E. et al. (Eur. J. Org. Chem. 2001,1371-1376), 2,2,6,6-tetramethylpiperidine (8.84 mL, 52 mmol, Aldrich) in50 mL of ether at 0° C. was charged with n-BuLi (33 mL, 52 mmol,Aldrich, 1.6 M hexanes). After stirring at 0° C. for 30 min, thesolution was cooled to −78° C. and charged with a solution of3,4-dichloropyridine (7.0 g, 47 mmol, Matrix) in 5 mL of ether. Afterstirring at −78° C. for 2 h, carbon dioxide (dry ice) was bubbled intothe reaction mixture via cannula at which time the solution becameheterogeneous. After bubbling carbon dioxide into the reaction at −78°C. for 10 min, the cooling bath was removed and the reaction mixture wasallowed to warm to room temperature, while continuing to bubble CO₂through the solution. The reaction was quenched with saturated aqueousammonium chloride solution (˜50 mL) and stirred at rt under anatmosphere of air for 5 min. The reaction mixture was diluted with water(˜150 mL) and extracted with ethyl acetate (2×75 mL) to remove anyremaining starting material. The aqueous layer was acidified to pH 1-2with 1N aqueous HCl solution and extracted with ethyl acetate (2×100mL). The organic phase was dried over anhydrous magnesium sulfate andconcentrated in vacuo to give 3,4-dichloropicolinic acid (3.5 g, 39%) asa yellow solid. ¹H NMR (DMSO-d₆) δ 8.53 (d, 1H, J=5.2 Hz), 7.90 (d, 1H,J=5.2 Hz); MS (ESI⁺) m/z 192.08 (M+H)⁺.

Step 2. Preparation of 3,4-Dichloropicolinamide

A solution of 3,4-dichloropicolinic acid (3.5 g, 18 mmol) in excessthionyl chloride (10 mL, Aldrich ReagentPlus 99.5%) was stirred at 80°C. for 1 h. After cooling to room temperature, the reaction mixture wasconcentrated in vacuo to remove excess thionyl chloride and thensuspended in ether (50 mL). The ethereal acid chloride solution wasadded to ammonium hydroxide (50 mL) at 0° C. The product was collectedby vacuum filtration, washed with water, and then triturated with etherto give 3,4-dichloropicolinamide (2.6 g, 76%) as a beige solid. m.p.174-175° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (d, 1H, J=5.2 Hz), 8.12(br s, 1H), 7.83 (d, 1H, J=5.2 Hz), 7.82 (br s, 1H); ¹³C NMR (100 MHz,DMSO-d₆) δ 166.2, 154.2, 147.9, 142.3, 126.1, 126.0; MS (ESI⁺) m/z191.10 (M+H)⁺.

Step 3. Preparation of 4-(4-Amino-2-fluorophenoxy)-3-chloropicolinamide

To a solution of 4-amino-2-fluorophenol (9.3 g, 73 mmol, 3B MedicalSystems, 3B3290) in DMF (100 mL) was added potassium tert-butoxide (8.8g, 79 mmol). After stirring at rt for 30 min, 3,4-dichloropicolinamide(10 g, 52 mmol) was added. The reaction mixture was stirred at 50° C.for 2.5 h. After cooling the reaction to rt, the mixture was dilutedwith 400 mL of ethyl acetate and washed with saturated aqueous sodiumbicarbonate solution (400 mL). The aqueous layer was back-extracted with300 mL ethyl acetate. The combined organic phases were washed with 10%aqueous lithium chloride solution, dried over anhydrous sodium sulfate,and concentrated in vacuo. The resulting brown solid was suspended inethyl acetate, filtered and washed with ether to give the product as atan solid (7.4 g). The filtrate was concentrated in vacuo and thenpurified by flash chromatography on silica gel (2% methanol/ethylacetate). The resulting brown solid was triturated with ether to give anadditional 4.3 g of 4-(4-amino-2-fluorophenoxy)-3-chloropicolinamide(79% combined yield) as a pale tan solid. m.p. 217-218° C.; ¹H NMR (400MHz, CD₃OD) δ 8.29 (d, 1H, J=5.6 Hz), 7.00 (t, 1H, J=8.8 Hz), 6.79 (d,1H, J=5.6 Hz), 6.63-6.55 (m, 2H); MS (ESI⁺) m/z 282.21 (M+H)⁺.

Step 4. Preparation of 4-Iodo-2-methoxynicotinaldehyde

To a solution of diisopropylamine (260 g, 2.57 mol) in anhydrous THF(6.5 L) at −30 to −40° C. under a blanket of N₂ was added n-BuLi (156 g,2.45 mol) dropwise via cannula. The resulting solution was allowed towarm to 0° C. and stirred at this temperature for 35 min. The solutionwas then cooled to −78° C. and 2-fluoropyridine (250 g, 2.57 mol, Alfa)was added dropwise. The reaction mixture was stirred at −78° C. for 2 h.This mixture was then added via cannula to a solution of iodine (654 g,2.57 mol) in anhydrous THF (1.96 L) at −20° C. under N₂. After thereaction was complete, the mixture was quenched with ice water andextracted with EtOAc. The organic layer was washed with sodiumthiosulfate followed by water and brine. The organics were then dried(Na₂SO₄) and concentrated in vacuo to give 2-fluoro-3-iodopyridine (450g, 78%) as a solid.

To a solution of diisopropylamine (345 mL, 249 g, 2.46 mol) in anhydrousTHF (5 L) at −8 to −10° C. under a blanket of N₂ was added n-BuLi (880mL, 158 g, 2.46 mol) dropwise via cannula. The mixture was stirred at−10° C. for 30 min, cooled to −78° C. and treated with a solution of2-fluoro-3-iodopyridine (500 g, 2.24 mol) in dry THF (2 L) dropwise.After the addition, the reaction mixture was warmed to −60° C. and thistemperature was maintained for 2 h. The mixture was then cooled to −78°C., treated with ethyl formate (183 g, 2.47 mol) dropwise, followed bysodium methoxide (149 g, 2.75 mol) in MeOH (1.5 L) and warmed to ambienttemperature. The reaction mixture was quenched with ice water andextracted with EtOAc. The layers were separated and the organic phasewas washed with water and brine, dried (Na₂SO₄) and concentrated invacuo. The residue was purified by flash chromatography on silica gel toafford 4-iodo-2-methoxynicotinaldehyde (380 g, 64%) as a solid.

Step 5. Preparation of 4-Iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde

4-Iodo-2-methoxynicotinaldehyde (25 g, 95 mmol) and sodium iodide (31.0g, 285 mmol, Aldrich) were stirred together in 500 mL of acetonitrile.To this solution was added chlorotrimethylsilane (36.0 mL, 285 mmol,Aldrich ≧99%) dropwise over 15 minutes. The reaction mixture was stirredfor 2 h at room temperature and then concentrated under vacuum. Theproduct was suspended in ethyl acetate, water, and saturated aqueoussodium bicarbonate, then filtered to give a dark brown solid. This solidwas triturated with acetonitrile to yield4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (21.3 g, 90%) as ayellow solid (mixture of tautomers). MS (ESI⁺) m/z 250.04 (M+H)⁺.

Step 6. Preparation of1-(4-Fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde

4-Iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (16.0 g, 64.3 mmol),4-fluorophenylboronic acid (26.8 g, 193 mmol, Aldrich), copper(II)acetate (23.4 g, 129 mmol, Aldrich), and myristic acid (58.7 g, 257mmol, Aldrich) were stirred together in 800 mL of toluene. To thissolution was added 2,6-lutidine (60 mL, 514 mmol, Aldrich) and thereaction was stirred vigorously for 1 day. An additional 5 g of4-fluorophenylboronic acid was added and the reaction was stirredvigorously for an additional 3 days. The reaction mixture wasconcentrated in vacuo and the resulting material was suspended in 10%methanol/ethyl acetate. Celite® was added and the mixture was stirredfor 5 minutes. Next the mixture was filtered through a plug of Celite®,concentrated in vacuo, and the resulting material was suspended in ethylacetate and water. The mixture was filtered through Celite® again toremove additional copper that had precipitated out, washing well withethyl acetate. The filtrate was washed with 1N aqueous HCl, dried oversodium sulfate, filtered, and concentrated under vacuum. The resultingsolid was triturated with ethyl acetate to yield 9.25 g (42%) of1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde as ayellow solid. The filtrate was concentrated in vacuo and the remainingsolid was triturated again with ethyl acetate to yield an additional5.75 g (68% total yield) of the desired product as a yellow solid. ¹HNMR (DMSO-d₆) δ 9.57 (s, 1H), 7.68 (d, 1H, J=7.2 Hz), 7.58-7.54 (m, 2H),7.40 (t, 2H, J=8.8 Hz), 7.02 (d, 1H, J=7.2 Hz); MS (ESI⁺) m/z 344.13(M+H)⁺.

Step 7. Preparation of1-(4-Fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid

1-(4-Fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (10.0g, 29.2 mmol) and sodium phosphate monobasic (10.1 g, 73 mmol, Aldrich)were stirred vigorously in 35 mL each of THF, tert-butanol, and water at0° C. 2-Methyl-2-butene (45.2 mL, 2.0 M in THF, Aldrich) was added tothe reaction mixture, followed by sodium chlorite (6.06 g, 67.1 mmol,Aldrich). The ice bath was removed and the reaction mixture was warmedto room temperature, stirring very rapidly. After a few minutes thedesired product began precipitating out of solution. Stirring wascontinued for 1 h, then 20 mL of 1N aqueous HCl was added, and stirringwas continued for another 5 minutes. The desired product was filteredoff, then washed with water, ethyl acetate, and ether. The filtrate wastaken and the layers were separated. The aqueous layer was extractedwith ethyl acetate. The combined organic layers were dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingsolid was suspended in ethyl acetate, filtered, and washed with ethylacetate and ether to yield additional desired product. The pale yellowsolids were combined to yield 8.22 g (78%) of1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid(92% pure, 8% starting material remaining). This material was dissolvedin a minimal amount of 1N aqueous NaOH. Ethyl acetate was added and themixture was stirred vigorously for 5 minutes. The layers were separated,and the aqueous layer was extracted with ethyl acetate. The aqueouslayer was acidified, with stirring, using concentrated HCl to pH 1. Thepale yellow solid that precipitated out of solution was collected,washed with water, ethyl acetate, diethyl ether and then dried undervacuum to afford 7.33 g (70%) of1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid(95.4% pure by HPLC). ¹H NMR (DMSO-d₆) δ 13.53 (s, 1H), 7.52-7.49 (m,3H), 7.38 (t, 2H, J=8.8 Hz), 6.81 (d, 1H, J=7.2 Hz); MS (ESI⁺) m/z360.14 (M+H)⁺.

Step 8. Preparation of3-Chloro-4-(2-fluoro-4-(1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamide

To a suspension of1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid(36.3 g, 101 mmol) in a mixture of 500 mL of DCM and 0.25 mL of DMF at0° C. was added oxalyl chloride (38.5 g, 26.5 ml, 303 mmol) dropwiseover 0.5 h. The reaction mixture became homogeneous after stirring atroom temperature for 2 h and was then concentrated in vacuo. Theresulting residue was resuspended in DCM (200 ml) and the mixture wasagain concentrated in vacuo to remove any remaining oxalyl chloride(performed twice). The crude acid chloride compound was then dried underhigh vacuum for 0.5 h. While the carboxylic acid chloride compound wasdrying, 4-(4-amino-2-fluorophenoxy)-3-chloropicolinamide (22.8 g, 81mmol) was dissolved in THF (200 mL) and DMF (50 mL). The solution wascooled to 0° C. and pyridine (12.8 g, 162 mmol) was added. A solution ofthe carboxylic acid chloride compound in 250 mL of DCM was then added tothe reaction mixture dropwise over 40 minutes. The cooling bath wasremoved and the reaction mixture was stirred at room temperature for 0.5h before being quenched with water (50 mL). The volatiles were removedunder reduced pressure until the volume was reduced to approximately 100mL. The contents of the flask were dissolved in EtOAc (1 L) and thesolution was washed sequentially with 1N HCl (2×200 mL), saturatedaqueous NaHCO₃ (2×200 mL), 10% aq. LiCl solution (3×200 mL) andsaturated aq. NaCl solution (200 mL). The organic phase was dried overanhydrous sodium sulfate, filtered through a pad of silica gel (washedwith 500 mL EtOAc) and the filtrate was concentrated in vacuo. The crudeproduct was triturated with MeOH (100 mL) and the solid was filtered,washed with MeOH (10 mL) and collected. The filtrate was concentrated invacuo and the trituration process was repeated. The two batches of solidwere combined, suspended in EtOH (100 mL) and concentrated in vacuo. Thesolid was again suspended in EtOH (50 mL) and concentrated in vacuo. Theresulting solid dried overnight under high vacuum to afford3-Chloro-4-(2-fluoro-4-(1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamide(40.3 g, 80%) as an off-white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.34 (d,1H, J=5.6 Hz), 7.92 (dd, 1H, J=12.4, 2.4 Hz), 7.51-7.47 (m, 4H),7.37-7.29 (m, 3H), 6.99 (d, 1H, J=7.2 Hz), 6.86 (d, 1H, J=5.6 Hz); MS(ESI⁺) m/z 623.08 (M+H)⁺.

Step 9. Preparation of3-Chloro-4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide

To a suspension of NaH (1.87 g, 77.9 mmol) in THF (26 mL) under nitrogenwas slowly added EtOH (80 mL, Aldrich>99.5%, 200 proof) and theresulting homogeneous solution was stirred for 10 minutes. The sodiumethoxide solution was then added to a mixture of3-Chloro-4-(2-fluoro-4-(1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamide(37.3 g, 59.9 mmol) in THF (100 mL) and EtOH (46 mL), and the resultingmixture was stirred at room temperature for 1 h before beingconcentrated in vacuo. The residue was suspended in water (500 mL) andthe mixture was sonicated and stirred for about 1 h at room temperatureuntil the remaining solid became a filterable powder. The resultingpowder was collected, triturated with ethyl ether (50 mL) and driedunder high vacuum for 48 h to afford3-Chloro-4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide(30.8 g, 95%) as a pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.34 (d,1H, J=5.6 Hz), 7.94 (dd, 1H, J=12.4, 2.4 Hz), 7.80 (d, 1H, J=8 Hz),7.48-7.46 (m, 3H), 7.31-7.28 (m, 3H), 6.86 (d, 1H, J=5.6 Hz), 6.61 (d,1H, J=7.2 Hz), 4.34 (q, 2H, J=7.2 Hz), 1.45 (t, 3H, J=7.2 Hz); MS (ESI⁺)m/z 541.11 (M+H)⁺.

Step 10. Preparation ofN-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

To a mixture of3-chloro-4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide(13.9 g, 25.7 mmol) in EtOAc (200 mL), MeCN (200 mL), and water (100 mL)at 0° C. was added iodobenzene diacetate (9.93 g, 30.8 mmol). Thereaction mixture was slowly warmed to room temperature and stirred for 1h. The resulting precipitate was filtered and washed with ethyl acetate.The combined filtrates were washed with saturated aqueous sodiumbicarbonate solution and the organic phase was dried over anhydroussodium sulfate and concentrated in vacuo. This residue and the originalprecipitate were combined and purified by flash chromatography (SiO₂,0-2% methanol/chloroform gradient elution) to giveN-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(9.8 g, 74%) as an off-white solid. ¹H NMR (DMSO-d₆) δ 10.57 (s, 1H),7.83-7.79 (m, 2H), 7.67 (d, 1H, J=5.6 Hz), 7.41-7.38 (m, 3H), 7.36-7.22(m, 3H), 6.44 (d, 1H, J=7.6 Hz), 6.36 (br s, 2H), 5.86 (d, 1H, J=6.0Hz), 4.18 (q, 2H, J=7.2 Hz), 1.23 (t, 3H, J=7.2 Hz); MS (ESI⁺) m/z513.09 (M+H)⁺.

TABLE 2 Comparison of Processes of Example 1 and Comparative Example 2Example 1 Comparative Example 2 Process (yield) (yield) Steps 1 to 3 toprepare 38% 23% aniline compound Steps 4-7 to prepare acid 32% 21%compound Coupling of acid and 81% 56% aniline compounds to (steps 8-9)(steps 8-10) prepare pyridinone compound Overall yield (based on 26% 12%acid compound as limiting reagent)

Example 3N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide

Preparation 3A: 3-Chloro-N-(diphenylmethylene)pyridin-2-amine

2,3-Dichloropyridine (105.00 g, 710 mmol), Pd(OAc)₂ (3.98 g, 17.74mmol), rac-BINAP (16.57 g, 26.61 mmol), cesium carbonate (346.76 g, 1065mmol), THF (1.05 L), and benzophenone imine (124.67 mL, 745 mmol) wereadded to a 2 L Chem-Glass Reactor fitted with a mechanical stirrer andreflux condenser. The mixture was heated to reflux with stirring for 18h. The material was filtered, washed with THF (100 mL). The resultingfiltrate was concentrated in vacuo to ⅓ volume and used without furtherpurification. ¹H NMR (CDCl₃) δ 6.79 (dd, 1H, J=4.6, 7.6 Hz), 7.19-7.60(m, 9H), 7.79-7.95 (m, 2H), 8.16 (dd, 1H, J=1.5, 5.1 Hz); MS (ESI⁺) m/z293.1 (M+H)⁺.

Preparation 3B: 3-Chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-one

To a 4-L Chemglass reactor (fitted with addition funnel, nitrogenblanket) was added: crude 3-chloro-N-(diphenylmethylene)pyridin-2-amineand triisopropyl borate (196.38 mL, 852 mmol). The resulting solutionwas the cooled to 0° C. In a separate reactor was added diisopropylamine(169.78 mL, 1207 mmol) and THF (1.05 L). This solution was cooled to 0°C. and n-butyl lithium (683.22 mL, 923 mmol) was added slowly. Afterstirring at 0° C., this solution was added slowly to the first solution.The reaction mixture was stirred for 30 min without the cooling bath(HPLC indicated consumption of starting material). Water (1.05 L) wasadded to the mixture, followed by the addition of sodium percarbonate(336.34 g, 1065 mmol) in one portion. This mixture was allowed to stirat 20° C. for 1 h. A saturated solution of NaHSO₃ (˜1 L) was addedslowly. The aqueous layer was removed and DMF (840.00 mL) was added tothe organic layer and the THF was distilled off (solvent swap from THFto DMF). The DMF was used without further purification. ¹H NMR (CDCl₃) δ6.02 (d, 1H, J=7.1 Hz), 7.10 (d, 1H, J=7.1 Hz), 7.20-7.80 (m, 10H); MS(ESL) m/z 309.07 (M+H)⁺.

Preparation 3C:3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine

To a 2-L Chem-Glass reactor was added the crude3-chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-one (from above, now inDMF) and cesium carbonate (300.52 g, 923 mmol) followed by the additionof 3,4-difluoronitrobenzene (118.15 mL, 1065 mmol). The mixture washeated to approximately 90° C. with stirring for 2 h. The mixture wascooled to 25° C. with stirring for 10 min. To this solution was addedwater (1 L). The mixture was extracted with EtOAc (1 L) and the aqueousphase was discarded. The organics were concentrated to afford an oil.The oil was dissolved into EtOH (200 mL) (heating sometimes required).After the solution was allowed to stand at 25° C. for 4 h, a solid wascollected by filtration to afford3-chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine(104.00 g; 32.73% yield) as a yellow solid. ¹H NMR (CDCl₃) δ 6.52 (d,1H, J=5.6 Hz), 6.80 (dd, 1H, J=8.1, 9.1 Hz), 7.21-7.60 (m, 8H),7.78-7.95 (m, 2H), 8.00 (m, 1H), 8.11 (dd, 1H, J=2.5, 9.6 Hz), 8.17 (d,1H, J=5.6 Hz); MS (ESL) m/z 448.01 (M+H)⁺.

Preparation 3D:4-(4-Amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine

The following materials were added to a 2-L Chem-Glass reactor:3-chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine(110.00 g, 221 mmol), isopropyl alcohol (990.00 mL), and ammoniumsulfide (˜40% in water, 297.00 mL, 2324 mmol). The mixture was allowedto stir at 20° C. for 3-4 h.3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-aminewas not detected by HPLC analysis. The reaction mixture was heated to70° C. and allowed to stir for 3-4 h. Once the reaction was complete,water (14 mL/g·LR) was added. The reaction mixture was cooled to 20° C.(reaction temp) over 1 h. Upon cooling a solid precipitated and wasfiltered off and washed with water (12.5 mL/g·LR), followed byheptane:MTBE (4:1; 5 mL/g·LR). After LOD (˜25%), 95.3 g of crude4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine(90AP) was obtained. The crude4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-aminewas dissolved into n-BuOAc (7 mL/g·LR) by heating to approximately 85°C. At 85° C., heptane (7 mL/g·LR) was added dropwise until the solutionbecame cloudy. The solution was then allowed to cool to 20° C. withstirring. Once at 20° C., the slurry was aged for 8 h. The solid wasfiltered, washed with heptane (5 mL/g·LR), and then dried overnight in avacuum oven at 60° C. to afford4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine(62.53 g; 67.69% yield) as a faint yellow solid. ¹H NMR (CDCl₃) δ 6.23(dd, 1H, J=1.0, 5.6 Hz), 6.43 (m, 1H), 6.49 (dd, 1H, J=2.5, 12.1 Hz),6.92 (t, 1H, J=8.6 Hz), 7.25-7.60 (m, 8H), 7.87 (m, 2H), 7.95 (d, 1H,J=6.1 Hz); MS (ESI⁺) m/z 418.6 (M+H)⁺.

Preparation 3E: Ethyl 4-(4-fluorophenyl)-3-oxobutanoate

To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid, 8.0g, 56 mmol) dissolved in anhydrous methylene chloride (100 mL) andpyridine (11 mL), at 0° C. under nitrogen atmosphere, was slowly added2-(4-fluorophenyl)acetyl chloride (7.6 mL, 9.6 g, 56 mmol). The redsolution was stirred at 0° C. for 1.5 h. The reaction mixture wastreated with 1 N HCl (13 mL) and diluted with methylene chloride (200mL). The layers were separated and the organic layer was washed withsaturated aqueous sodium chloride, dried and concentrated in vacuo togive 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione.The crude intermediate was suspended in absolute EtOH (150 mL) and theresulting mixture was refluxed for 4 hours. The solvent was then removedin vacuo and the residue was purified by flash column chromatography(SiO2, 230-400 mesh, 8:1 hexane-ethyl acetate gradient elution) toafford the desired product (4.6 g, 37%). 1H NMR (CDCl₃) δ 7.23-7.15 (m,2H), 7.05-6.98 (m, 2H), 4.18 (q, 2H, J=7.0 Hz), 3.81 (s, 2H), 3.46 (s,2H), 1.26 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 225 (M+H)+.

Preparation 3F:5-(4-Fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

To a solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (4.6 g, 21mmol) in absolute EtOH (45 mL) was added NaOEt solution (21% NaOEtsolution in EtOH, 7.7 mL) and triazine (1.67 g, 21 mmol). The resultingmixture was heated to 85° C. for 1.5 h, cooled to room temperature andtreated with an additional portion of triazine (0.08 g, 1 mmol) andNaOEt solution (21% NaOEt solution in EtOH, 0.4 mL). The reactionmixture was heated for an additional hour and concentrated in vacuo. Theresidue was treated with 1N HCl until the pH of the reaction was about2. The precipitate was collected to give the desired ester intermediate,ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (4.5 g,83%) as a yellow solid. MS (ESI⁺) m/z 262 (M+H)⁺.

The above ester (1.0 g, 3.8 mmol) was dissolved in 2N NaOH (20 mL) andheated to 65° C. for 2 h. The resulting clear mixture was cooled toambient temperature and the solids were filtered off. The filtrate wasthen acidified with 1N HCl to pH=1 and the resulting yellow precipitatewas collected as the desired product (0.73 g, 82%). ¹H NMR (DMSO-d₆) δ13.52 (br s, 1H), 8.86 (s, 1H), 8.51 (s, 1H), 7.99-7.96 (m, 2H),7.55-7.51 (m, 2H); MS (ESI⁺) m/z 234 (M+H)⁺.

Preparation 3G:N-(4-(3-Chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide

To a solution of4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine(836 mg, 2.0 mmol) and5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (490 mg,2.0 mmol) in DMF (10 mL) at room temperature were added HATU (913 mg,2.4 mmol) and DIPEA (1.05 ml, 6.0 mmol). The reaction mixture wasstirred at room temperature for 3 h prior to being quenched by theaddition of cold water (50 mL). The solid that formed was collected byfiltration, and washed with water and ether. The solid was dissolved inDCM and purified by flash column chromatography (SiO₂, DCM to 10% MeOHin DCM) to give the desired product (987 mg, 78%) as a light yellowsolid. MS (ESI⁺) m/z 633 (M+H)⁺.

Example 3

To a solution ofN-(4-(3-chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide(410 mg, 0.65 mmol) in THF (10 mL) at room temperature was added aqueousHCl (2 M, 0.81 mL, 1.62 mmol). The reaction mixture was stirred at roomtemperature for 1 h and then concentrated in vacuo. Cold 5% aq. NaHCO₃(5 mL) was then added to the residue. The solid that formed wascollected by filtration, washed with water and then ether, and driedunder vacuum to give the desired product (275 mg, 90%). ¹H NMR (DMSO-d₆)δ 13.31 (s, 1H), 12.70 (br s, 1H), 8.63 (d, 1H, J=1.30 Hz), 8.09 (d, 1H,J=1.50 Hz), 8.02 (dd, 1H, J=2.50, 13.10 Hz), 7.76 (d, 1H, J=5.50 Hz),7.71 (m, 2H), 7.44 (dd, 1H, J=1.50, 8.80 Hz), 7.31 (t, 1H, J=8.80 Hz),7.27 (t, 2 H, J=8.80 Hz), 6.43 (br s, 2H), 5.96 (d, 1H, J=5.60 Hz); MS(ESI⁺) m/z 469 (M+H)⁺.

N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide,hydrochloride salt

The HCl salt ofN-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide(Example 3) is obtained by treating a solution ofN-(4-(3-chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide(Preparation 3G) in THF with excess aqueous HCl at room temperature. Thevolatiles are removed in vacuo to provide the desired compound.

Example 4 Alternative Synthesis of3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-aminePreparation 4A: 2,3-dichloropyridin-4-ol

A first solution was prepared by dissolving 2,3-Dichloropyridine (100 g,0.68 mol) and triisopropyl borate (315 mL, 1.37 mol) in THF (150 mL).The resulting solution was cooled to −10° C. In a separate reactor, asecond solution was prepared by dissolving diisopropylamine (150 mL,1.07 mol) in THF (500 mL). The second solution was cooled to −10° C. andunder nitrogen, n-butyl lithium (420 mL, 1.05 mol) was added over 20min. After stirring for 10 min, the second solution was added slowly tothe first solution via vacuum transfer.

The reaction mixture was stirred for 3 hrs at 22° C. until HPLC analysisindicated reaction completion. Water (1.00 L) was added to the mixture,followed by addition of sodium percarbonate (238 g) in two portions. Theresulting mixture was allowed to stir at 20° C. for 1 h. The pH of themixture was adjusted to pH 2-3 by addition of conc. HCl (300 mL). Next,solid NaHSO₃ (85 g) was added. The aqueous layer was separated andextracted with toluene (150 mL). The combined organic layers were washedwith water (two times 100 mL) and concentrated by atmosphericdistillation (distillation temperature up to 90° C.) to about 500 mL.The resulting slurry was cooled to 20° C. and filtered on a Buechnerfunnel. The cake was washed with heptane (two times 100 mL) andsubsequently dried to yield 100.9 g (91%) of 2,3-dichloropyridin-4-ol aswhite solid.

Preparation 4B: 2,3-dichloro-4-(2-fluoro-4-nitrophenoxy)pyridine

To a 2-L Chem-Glass reactor was added 2,3-dichloropyridinol (90 g, 0.55mol), 3,4-difluoronitrobenzne (100 g, 0.63 mol), lithium carbonate (59.4g, 0.80 mol) and dimethyl sulfoxide (360 mL). The mixture was heated to115° C. for 21 hrs, until the reaction was deemed complete by HPLCanalysis. The mixture was cooled to 25° C. and methanol (180 mL) wasadded, followed by water (960 mL). The mixture was neutralized byaddition of conc. HCl (60 g) and the resulting slurry was stirred at 35°C. for 1 h. After cooling to 28° C., the slurry was filtered on aBuechner funnel and the filter cake was washed with water (four times250 mL). The crude cake was then suspended in methanol (20 mL) and water(250 mL), and the resulting mixture was stirred for 20 min at 45° C.After cooling to 25° C., the slurry was filtered. The resulting cakewashed with heptane (two times 75 mL) and dried under vacuum to yield164.68 g (99%) of 2,3-dichloro-4-(2-fluoro-4-nitrophenoxy)pyridine asyellow solid.

Preparation 4C:3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine

To a 2,5-L Chem-Glass reactor was added2,3-dichloro-4-(2-fluoro-4-nitrophenoxy)pyridine (50 g, 0.165 mol),benzoimine (30 g, 0.165 mol), cesium carbonate (110 g, 0.321 mol),palladium acetate (0.9 g, 4.0 mmol), racemic2,2′-bis(diphenylphosphino)1,1′-binaphthyl (3.25 g, 5.1 mmol), andxylene (300 mL). The mixture was heated to 125° C. for 11 hrs. Themixture was cooled to 50° C. and silicagel (20 g) and xylene (300 mL)were added. The suspension was stirred for 30 min at 50-55° C. andfiltered on a Buechner funnel. The filter cake was washed with xylene(two times 100 mL). The filtrates were combined, washed with water (twotimes 150 mL) and concentrated to about 150 mL by distillation on arotary evaporator. After cooling to 25° C., heptane (300 mL) was addedto the mixture. The resulting slurry was stirred at 25° C. for 16 hrs.Additional heptane (150 mL) was added to the slurry and the slurry wasfiltered on a Buechner funnel. The cake was washed with a mixture ofxylene 1:10 heptane (100 mL), followed by n-heptane (two times 100 mL).After drying under vacuum, 47.41 g (64%) of3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-aminewas obtained. ¹H NMR (CDCl₃) δ; MS (ESI⁺) m/z (M+H)⁺.

1. A process for preparing a compound of Formula (I):

comprising the steps of: (a) reacting a carboxylic acid compound ofFormula (III):

or an activated carboxylic acid compound thereof, and an anilinecompound of Formula (II):

wherein PAm is a protected amine group, to provide a compound of Formula(IV):

and (b) converting said protected amine group attached to said compoundof Formula (IV) to an amine group to provide said compound of Formula(I); wherein: G is

each R¹ is independently alkyl, haloalkyl, halogen, or CN; each R² isindependently alkyl, haloalkyl, halogen, or CN; R³ is phenyl substitutedwith alkyl, haloalkyl, halogen, or CN; each R⁴ is independently alkyl,haloalkyl, alkoxy, halogen, or CN; m is zero, 1, 2, 3, or 4; n is zero,1, 2, or 3; p is zero, 1 or 2; and q is zero, 1, 2, or
 3. 2. The processaccording to claim 1 wherein said step (a) comprises reacting saidactivated carboxylic acid compound of Formula (III).
 3. The processaccording to claim 1 wherein: PAm is —NH—R^(b), —NHC(O)OR^(a),—NHC(═O)R^(a), —NH(CH₂R^(c)), —NHSi(R^(d))₃, —NH(PO(OR^(d))₂,—NHSO₂R^(e), —N(R^(b))₂, —N(C(O)OR^(a))₂, —N(C(O)R^(a))₂, —N(CH₂R^(c))₂,—N(Si(R^(d))₃), —N═C(R^(a))₂, or

each R^(a) is independently H, alkyl, haloalkyl, benzyl, and/or aryl;each R^(b) is independently alkyl, haloalkyl, benzyl, methoxybenzyl,and/or aryl; each R^(c) is independently allyl or alkoxy; each R^(d) isindependently alkyl; R^(e) is alkyl, alkyl substituted with —Si(alkyl)₃,phenyl, or nitrophenyl; and each R^(f) is independently alkyl and/orbenzyl.
 4. The process according to claim 1 wherein said anilinecompound of Formula (II) is:


5. The process according to claim 4 wherein said carboxylic acidcompound of Formula (III) is:


6. The process according to claim 5 wherein PAm is:


7. The process according to claim 1, wherein: said compound of Formula(I) is:

said aniline compound of Formula (II) is:

said carboxylic acid compound of Formula (III) is:

and said compound of Formula (IV) is:


8. The process according to claim 1, wherein: said compound of Formula(I) is:

said aniline compound of Formula (II) is:

said carboxylic acid compound of Formula (III) is:

and said compound of Formula (IV):


9. A compound having the structure:

or a salt thereof, wherein: X is NO₂ or NH₂; and PAm is a protectedamine group.
 10. The compound according to claim 9, or a salt thereof,wherein: PAm is


11. The process according to claim 8, further comprising the step ofconverting said compound of Formula (I) to a prodrug having thestructure:


12. A compound of Formula (Ia):

prepared according to the process of claim
 1. 12. A compound of Formula(Ib):

prepared according to the process of claim 1.